非甾体类消炎药对胃黏膜的损伤及替普瑞酮预防作用的实验研究

目的建立大鼠非甾体类消炎药(NSAID)胃病模型,观察替普瑞酮对NSAID胃病的预防作用。方法成年雄性SD大鼠91只,分为生理盐水组、NSAID组(Ⅰ)、替普瑞酮组(Ⅱ)。后两组再分为如下亚组Ⅰa组(吲哚美辛5mg.kg-1.d-1)、Ⅰb组(吲哚美辛5mg.kg-1.d-1及泼尼松10mg.kg-1.d-1),Ⅰc组(塞来昔布100mg.kg-1.d-1),Ⅰd组(塞来昔布100mg.kg-1.d-1及泼尼松10mg.kg-1.d-1)Ⅱa组(替普瑞酮12mg.kg-1.d-1,吲哚美辛5mg.kg-1.d-1)Ⅱb组(替普瑞酮12mg.kg-1.d-1,吲哚美辛5mg.kg-1.d-1及泼尼松10mg.kg-1.d-1),Ⅱc组(替普瑞酮12mg.kg-1.d-1,塞来昔布100mg.kg-1.d-1),Ⅱd组(替普瑞酮12mg.kg-1.d-1,塞来昔布100mg.kg-1.d-1及泼尼松10mg.kg-1.d-1)。每组连续用药4d后观察损伤指数(LI)和病理组织学变化(Whittle评分),评价胃黏膜损伤情况。同时用RT-PCR检测环氧合酶(COX)同工酶表达情况。结果Ⅰ组的LI(除Ic外)(11.00(1.00~22.5)、8.50(0.75~14.50)、11.00(3.50~14.75),P<0.01)及Whittle评分均比生理盐水组显著降低(1.00(0.00~1.25)、2.00(0.00~5.00)、1.00(0.00~3.00)、2.00(0.00~2.00),P<0.01);Ⅱ各亚组的LI(0.00(0.00~0.25)、1.00(0.00~1.50)、0.00(0.00~0.00)、0.00(0.00~1.00),P<0.05)及Whittle评分比相应的Ⅰ组显著降低(0.00(0.00~0.00)、0.00(0.00~0.50)、0.00(0.00~0.25)、0.00(0.00~0.50),P<0.05);Ⅰc与Ⅰa组间和Ⅰd与Ⅰc组间比较,LI差异有统计学意义(P<0.05)。Ⅰ组(除Ⅰc外)和Ⅱ组(除Ⅱc外)的胃黏膜COX-1表达比生理盐水明显减少(0.384±0.031、0.354±0.026、0.753±0.049、0.366±0.035、0.381±0.036、0.766±0.401,P<0.001),而Ⅰa、Ⅰb、Ⅱa、Ⅱb组COX-2mRNA表达明显增多(0.483±0.056、0.448±0.046、0.461±0.050、0.479±0.032,P<0.001)。Ⅰ亚组和Ⅱ亚组组间比较COX差异无统计学意义。结论COX-2抑制剂有胃黏膜损伤作用,但轻于传统NSAID;糖皮质激素泼尼松能加重NSAID胃病;NSAID胃病的发病机制除了COX-1抑制外,可能有其他因素参与其中;替普瑞酮能有效预防NSAID胃病,但作用机制可能与COX的表达无关。

Non-steroidal anti-inflammatory drug induced gastropathy and preventive effects of teprenone on the gastropathy in rats

OBJECTIVE: To construct the model of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and observe the preventive effects of Teprenone on it in rats. METHODS: Ninety-one male Sprague-Dawley (SD) rats were divided into normal saline group, model group (I) and prophylaxis group (II). Group I includes four subgroups (Ia, Ib, Ic, Id) treated by indomethacin (5 mgxkg(-1)xd(-1)), combination of indomethacin (5 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)), celecoxib (100 mgxkg(-1)xd(-1)) and combination of celecoxib (100 mgxkg(-1)xd(-1)) and prednisone (10 mgxkg(-1)xd(-1)) respectively. Group II also includes four subgroups (IIa, IIb, IIc, IId) pretreated by teprenone (12 mgxkg(-1)xd(-1)) compared with group I. Lesion index (LI), pathohistology index, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) mRNA detected by RT-PCR were observed after 4 days. RESULTS: Compared with normal saline group, LI (11.00 (1.00 - 22.5), 8.50 (0.75 - 14.50), 11.00 (3.50 - 14.75), P < 0.01) of three model subgroups (Ia, Ib, Id), and pathohistology indexes (1.00 (0.00 - 1.25), 2.00 (0.00 - 5.00), 1.00 (0.00 - 3.00), 2.00 (0.00 - 2.00), P < 0.01) of the whole model group increased significantly (P < 0.05). Compared with corresponding model subgroups, LIs (0.00 (0.00 - 0.25), 1.00 (0.00 - 1.50), 0.00 (0.00 - 0.00), 0.00 (0.00 - 1.00), P < 0.05) and pathohistology indexes (0.00 (0.00 - 0.00), 0.00 (0.00 - 0.50), 0.00 (0.00 - 0.25), 0.00 (0.00 - 0.50), P < 0.05) of prophylaxis subgroups were decreased significantly (P < 0.05). There was obvious difference in LI between Ic and Ia as well as between Ic and Id (P < 0.05). Compared with normal saline group, COX-1 mRNA expression of the groups (Ia, Ib, Id, IIa, IIb and IId) increased (0.384 +/- 0.031, 0.354 +/- 0.026, 0.753 +/- 0.049, 0.366 +/- 0.035, 0.381 +/- 0.036, 0.766 +/- 0.401, P < 0.001) while COX-2 mRNA expression of the above groups decreased statistically (0.483 +/- 0.056, 0.448 +/- 0.046, 0.461 +/- 0.050, 0.479 +/- 0.032, P < 0.001). CONCLUSIONS: These results suggested gastric mucosa lesions could be resulted from COX-2 inhibitors but better than those induced by traditional NSAID. Prednisone could promote the risk in NSAID induced gastropathy. In addition to COX-1 inhibition, other factors might also involved in NSAID induced gastropathy. Teprenone could prevented from NSAID induced gastropathy but the actions might be not associated with COXs.